HLA-independent T cell receptors for targeting tumors with low antigen density

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Chimeric antigen receptors (CARs) are crucial for potent immune responses against cancer.
• Tumor escape due to low target antigen expression limits CAR efficacy.
• Novel strategies are needed to enhance T cell-mediated tumor recognition.

Purpose of the Study:

• To engineer T cells with enhanced antigen sensitivity beyond current CAR designs.
• To develop HLA-independent T cell receptors (HIT receptors) for improved cancer targeting.
• To assess the efficacy of HIT receptors in preclinical cancer models.

Main Methods:

• Editing the TRAC locus in human T cells to create HIT receptors.
• Reconfiguring T cell receptor-CD3 complex with CAR-matched immunoglobulin chains.
• Evaluating HIT T cell sensitivity and tumor recognition in vitro and in vivo.
• Augmenting HIT T cell persistence with coexpressed CD80 and 4-1BBL.

Main Results:

• HIT receptors provide high antigen sensitivity, surpassing CD28-based CARs.
• HIT receptors enable tumor recognition even with low target antigen expression.
• Functional persistence of HIT T cells is enhanced by CD80 and 4-1BBL coexpression.
• HIT receptors demonstrated efficacy in xenograft models of B cell leukemia and acute myeloid leukemia.

Conclusions:

• HIT receptors represent a significant advancement in T cell-based cancer immunotherapy.
• These receptors offer superior antigen sensitivity and overcome limitations of low antigen expression.
• HIT receptors are well-suited for targeting cell surface antigens with low abundance, improving therapeutic outcomes.